A comparison of the safety and efficacy of tapinarof and roflumilast topical therapies in the management of mild‐to‐moderate plaque psoriasis

Abstract Introduction Psoriasis is an immune‐mediated inflammatory skin disease. First‐line topical treatments include steroids, calcineurin inhibitors, vitamin D analogs, and anthralin. Recently, novel topical therapeutics like tapinarof and roflumilast have emerged with unique anti‐inflammatory mechanisms and promising efficacy profiles. Materials and methods This review utilized PubMed, SCOPUS, and Web of Science databases to identify recent studies on tapinarof and roflumilast. Criteria focused on efficacy, safety profiles, and therapeutic roles in psoriasis treatment. Results Four primary literature articles were identified for tapinarof and five for roflumilast. Both drugs demonstrated strong efficacy with minimal adverse events in treating mild‐to‐moderate plaque psoriasis. Tapinarof showed more frequent but mild adverse effects, while roflumilast had less frequent but more severe side effects. Discussion Tapinarof and roflumilast offer once‐daily dosing and successful treatment in restricted areas, potentially enhancing patient adherence. Cost remains a limiting factor, necessitating future comparative studies to evaluate the efficacy, safety, and cost‐effectiveness between the two drugs. Conclusion Tapinarof and roflumilast present promising topical treatments for psoriasis, showing efficacy and manageable safety profiles. Further research is crucial to fully elucidate their comparative benefits and drawbacks in clinical practice.


F I G U R E 1
Tapinarof and Roflumilast mechanism of action.Left: Tapinarof binds to and activates aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor, in the cytoplasm.The now-activated AhR-tapinarof complex heterodimerizes with the AhR nuclear translocator (ARNT).The AhR-tapinarof/ARNT complex induces gene expression that leads to the downregulation of proinflammatory cytokines, including interleukin (IL) 17, which is involved in the pathogenesis of psoriasis.Right: Roflumilast inhibits the phosphodiesterase-4 (PDE-4) isoenzyme, consequently increasing intracellular concentrations of the secondary messenger cyclic adenosine monophosphate (cAMP) in affected cells.This suppresses inflammation through a decreased release of inflammatory cytokines.inflammatory pathways implicated in psoriasis (Figure 1). 2,3The Food and Drug Administration (FDA) has approved topical roflumilast for plaque psoriasis treatment in patients aged 12 and older. 4The review aims to assess and compare the efficacy and safety of these treatments to guide clinicians and researchers in selecting optimal management strategies for mild-to-moderate plaque psoriasis.

MATERIALS AND METHODS
We conducted a literature review utilizing Pubmed, SCOPUS, and Web of Science databases to gather recent articles focusing on tapinarof and roflumilast for psoriasis treatment.Using the NLM Medical Subject Heading (MeSH) to derive search terms, we constructed strings including ("tapinarof" OR "roflumilast") AND ("psoriasis") AND ("adverse effects") AND ("efficacy").
Inclusion criteria were defined as articles involving primary data (e.g., randomized controlled trials, cohort studies, retrospective stud-

Tapinarof efficacy
Robbins et al. report the findings of a phase 2 clinical trial on the efficacy of the application of 0.5% and 1% tapinarof cream once or twice daily therapy for adults with plaque psoriasis (Table 1).This Psoriasis Area and Severity Index (PASI).Tapinarof was found to statistically improve psoriasis lesions in both concentration groups and duration groups as measured by PGA and PASI (p < 0.001, p < 0.05). 5provement measured by PGA was maintained for 4 weeks posttreatment.Clinical improvements were noted approximately 2 weeks post-treatment initiation. 5ein-Gold et al. reported additional outcomes of the same study, including Psoriasis Symptom Diary (PSD) scores and the patients' impressions of symptom severity and pruritus. 6The PSD tool is a validated, self-reported tool specific for psoriasis and uses 16 ± 6 questions to assess subjective measures of psoriasis symptoms. 7The PSD scores in the tapinarof-treated cohort were significantly reduced compared to the vehicle control (p < 0.05). 6Patient-reported severity scores and subjective measures of pruritis were also significantly improved in all tapinarof-treated groups compared to vehicle controls (p < 0.05). 6bwohl Results from PSOARING 3, the phase III trial includes 1-year safety and efficacy of tapinarof for plaque psoriasis are reported in Strober et al.In this trial, patients had to have completed 12 weeks with tapinarof or the vehicle as described in aforementioned trials, PSOARING 1 and 2. 9 These patients, of which 763 participated, were eligible for an additional 40 weeks of treatment, totaling 52 weeks.This trial showed that 1% concentration cream had continued improvement beyond 12 weeks and was well tolerated up to 52 weeks.Overall, 40.9% of participants achieved a complete disease clearance, measured as PGA of 0. 9 Remission was achieved for an average of 4 months for patients who had achieved PGA of 0 during any time point in the trial.Further, regarding patient-reported satisfaction, 85.8% reported satisfaction with the ease of managing their psoriasis with tapinarof, and 62.9% of patients indicated agreeing that the drug cleared their lesions and prevented recurrence. 10

Tapinarof safety profile
Phase 2 trials did not identify statistically significant adverse effects stemming from tapinarof use, as measured by both investigatorreported and patient-reported tolerability scores. 646% of patients experienced mild-moderate adverse effects, and 68% came from the 1% twice-daily cohort.Folliculitis, contact dermatitis, and other application site dermatitis were the most commonly reported.Contact dermatitis was the most common reason for treatment discontinuation, seen in 3% of participants. 5The safety profile and tolerability of tapinarof are well documented in the PSOARING trials.PSOARING TEAEs were limited to the application site, with no differences between drug and vehicle; application site erythema and pain, nasopharyngitis, and muscle strain were reported.
No patient discontinuation due to ADEs.17.8%, respectively) and contact dermatitis (5.0% and 5.8%, respectively).Of these, folliculitis severity led to discontinuation (1.8% and 0.9%), and contact dermatitis led to discontinuation (1.5% and 2.0%). 8ditional reported findings included headache (3.8% in both trials). 8e incidence of patient-reported burning, stinging, or pruritus was low.The most commonly reported adverse events following prolonged use of tapinarof were noted to be similar to short-term use.In the PSOARING 3 trials, 27.5% of participants reported adverse effects, the most common being folliculitis and contact dermatitis.Of these, discontinued use was reported in 1.2% and 1.4% of patients secondary to folliculitis and contact dermatitis, respectively. 9in the treatment of psoriasis. 12The primary outcome of a clear or almost clear IGA score at week 6 was observed in 28% of the patients in the roflumilast 0.3% group, in 23% in the roflumilast 0.15% group, and 8% in the placebo group (p < 0.001). 12The mean baseline PASI scores (a secondary outcome measure) were 7.7 in the roflumilast 0.3% group, 8.0 in the roflumilast 0.15% group, and 7.6 in the vehicle group (range, 0 to 72, with higher scores indicating worse disease). 12colas et al. also summarize roflumilast efficacy and safety in the DERMIS-1 and DERMIS-2 clinical trials.The IGA success rate of 42.4% with roflumilast 0.3% cream compared to 6.1% with the vehicle in DERMIS-1 (32.3%−46.9%;p < 0.001), and the IGA success rate of 37.5% with roflumilast 0.3% cream compared to 6.9% with the vehicle in DERMIS-2 (20.8%−36.9%;p < 0.001) indicates the statistically significant efficacy of roflumilast. 4Overall, topical roflumilast cream has shown to be effective in treating sensitive, intertriginous areas, and may be a good alternative to existing systemic therapy with far more notable adverse events. 4pp et al. assessed the safety and efficacy of roflumilast in a phase 1/2a study comprising a single-dose, open-label cohort of 0.5% roflumilast cream applied to 25 cm 2 psoriatic plaques (cohort 1), and a 28-day, double-blinded cohort with 1:1:1 randomization to 0.5% or 0.15% roflumilast cream, or the vehicle (cohort 2). 13The primary efficacy endpoint was met for both 0.5% or 0.15% roflumilast cream doses as demonstrated by Target Plaque Severity Score [TPSS] × Target Plaque Area [TPA]) improvement at week 4, which was statistically significant for roflumilast 0.5% (p = 0.0007) and 0.15% (p = 0.0011) versus the placebo.For both roflumilast doses, 66%−67% improvement from the baseline was observed at week 4, as opposed to 38% improvement for the vehicle.A post-hoc analysis of the aforementioned phase 2b clinical trial to evaluate the tolerability and efficacy of roflumilast cream when applied daily for 331 patients, of which 160 (48%) had psoriasis involving the face and/or intertriginous areas. 13At week 6, an IGA of 0 to 1 was met by patients receiving roflumilast (roflumilast 0.3%, 27.2%; roflumilast 0.15%, 22.3%; vehicle, 6.3%; nominal P ≤ 0.026).The percentage of patients with an IGA of 0 to 1 plus a two-grade improvement was also higher for the patients treated with roflumilast 0.3% at weeks 6, 8, and 12 and in those treated with roflumilast 0.15% at weeks 8 and 12 (nominal p < 0.05). 14Overall, it can be concluded that once-daily application of roflumilast cream is associated with a high efficacy and tolerability profile at both 0.5% and 0.15% doses when compared to existing topical therapies for chronic plaque psoriasis.

Roflumilast safety profile
Roflumilast exhibits tolerability and safety with minimal risk of adverse events.The incidence of treatment-emergent adverse events (TEAE) in the DERMIS trials was 25.2% with roflumilast in contrast to 23.5% with placebo in trial 1, and 25.9% with roflumilast when compared to 18.4% with placebo in trial 2. 11 The incidence of serious adverse events (SAE) was the same with roflumilast and vehicle in trial 1, and 0% with roflumilast versus 0.7% with the vehicle in trial 2. 11 Approximately 1% of patients discontinued treatment with roflumilast due to adverse reactions compared with 1.3% treated with the placebo.The most common TAE seen with roflumilast was urticaria at the application site experienced by 0.3% of participants. 4In a phase 2 study by Gooderham et al., TEAE occurred in 2 (2.2%) patients receiving roflumilast, including mild rash and moderate application site pain, and only 1 (1.1%) patient discontinued the study due to a drug-related AE. 15 Additional reported adverse effects included diarrhea (3.1%), headaches (2.4%), and insomnia (1.4%) in DERMIS 1, 16,17 and application site erythema and pain, nasopharyngitis, and muscle strain were additionally reported. 13,17,18

Clinical relevance
Existing topical treatments for psoriasis (steroids, vitamin D derivatives, TCIs) are limited by adverse effects.Tapinarof and roflumilast offer non-steroidal options, preferred by patients for ease of use.Tapinarof allows chronic use with limited site restrictions, 19 and showing 4-month efficacy. 20Roflumilast is effective in intertriginous areas, with once-daily dosing. 16Tapinarof lacks data on combination therapy and specific patient populations.Both drugs are costly, with tapinarof at $1405 20 and roflumilast at $825 16 , posing challenges in adherence.
Roflumilast lacks data on hepatic disease. 16Direct comparator studies between tapinarof and roflumilast are needed to ascertain the clinical outcomes, safety, and efficacy of one over the other.

CONCLUSION
Both tapinarof 1% cream and roflumilast 0.3% cream effectively treat mild-to-moderate plaque psoriasis with minimal adverse events, improving compliance with their water-based formulations.Tapinarof has more frequent but less severe side effects compared to roflumilast.However, their high cost and prior authorization requirements limit accessibility.Further research, especially in pediatric populations, is necessary to evaluate long-term efficacy and tolerability.

F I G U R E 2
Study selection process.randomized, double-blind multicenter study included 175 participants who completed a 12-week treatment.In the study, treatment success was measured by the Physician Global Assessment (PGA) score of 0 or 1, and additional outcomes included >75% improvement in Lebwohl and Kircik et al. postulated the superior efficacy of roflumilast 0.3% cream compared to the placebo in the treatment of chronic plaque psoriasis based on the results from two phase 3, randomized, double-blind, controlled, multicenter trials (DERMIS-1 [trial 1; n = 439] and DERMIS-2 [trial 2; n = 442]).Patients with ages 12 years and older with 2% to 20% of body surface area consisting of plaque psoriasis were randomized in a 2:1 ratio to receive roflumilast cream, 0.3% (trial 1: n = 286; trial 2: n = 290), or vehicle cream (trial 1: n = 153; trial 2: n = 152) once daily for 8 weeks.The primary endpoint was the Investigator Global Assessment (IGA) score improvement from the baseline (score range, 0-4) at week 8, along with 9 secondary outcomes, including intertriginous IGA success, 75% reduction in PASI score, and Worst Itch Numeric Rating Scale score of 4 or higher at baseline achieving a 4-point reduction (WI-NRS success) at week 8.The Roflumilast cohort demonstrated a statistically significant increase in IGA success percentages at week 8 than the vehicle cohort (trial 1: 42.4% vs. 6.1% [95% CI, 32.3%−46.9%];trial 2: 37.5% vs. 6.9% [95% CI, 20.8%−36.9%];p < 0.001 for both).Statistically significant differences favoring roflumilast over placebo were observed for 8 out of 9 secondary endpoints in trial 1, and all 9 secondary endpoints in trial 2, demonstrating the superior efficacy of roflumilast. 11Results from a double-blind, phase 2b study by Lebwohl and Papp et al.where adults with plaque psoriasis were randomly assigned to use roflumilast 0.3% cream, roflumilast 0.15% cream, or placebo once daily for 12 weeks also concluded the potency of roflumilast cream Summary of primary studies included in this review.
8 and 2 identified no significant differences between the treatment and vehicle cohorts regarding laboratory values, vitals, physical exam findings, or electrocardiogram measures.8Justover half of the participants in each trial (50.3% and 54.5%, respectively) reported adverse effects, with the most commonly reported being folliculitis (23.5%, TA B L E 1